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1.
Hum Mutat ; 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595648

RESUMO

We report 281 individuals carrying a pathogenic recurrent NF1 missense variants at p.Met1149, p.Arg1276 or p.Lys1423, representing three non-truncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% CI, 20.5%-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276 or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared to the "classic" NF1-affected cohorts (all P<0.0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all P<0.0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (P<0.0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population. This article is protected by copyright. All rights reserved.

3.
Genes (Basel) ; 10(9)2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466283

RESUMO

Neurofibromatosis Type 1 (NF1) is caused by pathogenic variants in the NF1 gene encoding neurofibromin. Definition of NF1 protein-protein interactions (PPIs) has been difficult and lacks replication, making it challenging to define binding partners that modulate its function. We created a novel tandem affinity purification (TAP) tag cloned in frame to the 3' end of the full-length murine Nf1 cDNA (mNf1). We show that this cDNA is functional and expresses neurofibromin, His-Tag, and can correct p-ERK/ERK ratios in NF1 null HEK293 cells. We used this affinity tag to purify binding partners with Strep-Tactin®XT beads and subsequently, identified them via mass spectrometry (MS). We found the tagged mNf1 can affinity purify human neurofibromin and vice versa, indicating that neurofibromin oligomerizes. We identify 21 additional proteins with high confidence of interaction with neurofibromin. After Metacore network analysis of these 21 proteins, eight appear within the same network, primarily keratins regulated by estrogen receptors. Previously, we have shown that neurofibromin levels negatively regulate keratin expression. Here, we show through pharmacological inhibition that this is independent of Ras signaling, as the inhibitors, selumetinib and rapamycin, do not alter keratin expression. Further characterization of neurofibromin oligomerization and binding partners could aid in discovering new neurofibromin functions outside of Ras regulation, leading to novel drug targets.

4.
Am J Hum Genet ; 104(6): 1088-1096, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31104772

RESUMO

Conceptual frameworks are useful in research because they can highlight priority research domains, inform decisions about interventions, identify outcomes and factors to measure, and display how factors might relate to each other to generate and test hypotheses. Discovery, translational, and implementation research are all critical to the overall mission of genomic medicine and prevention, but they have yet to be organized into a unified conceptual framework. To fill this gap, our diverse team collaborated to develop the Genomic Medicine Integrative Research (GMIR) Framework, a simple but comprehensive tool to aid the genomics community in developing research questions, strategies, and measures and in integrating genomic medicine and prevention into clinical practice. Here we present the GMIR Framework and its development, along with examples of its use for research development, demonstrating how we applied it to select and harmonize measures for use across diverse genomic medicine implementation projects. Researchers can utilize the GMIR Framework for their own research, collaborative investigations, and clinical implementation efforts; clinicians can use it to establish and evaluate programs; and all stakeholders can use it to help allocate resources and make sure that the full complexity of etiology is included in research and program design, development, and evaluation.

5.
Pediatrics ; 143(5)2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31010905

RESUMO

Neurofibromatosis type 1 (NF1) is a multisystem disorder that primarily involves the skin and peripheral nervous system. Its population prevalence is approximately 1 in 3000. The condition is usually recognized in early childhood, when pigmentary manifestations emerge. Although NF1 is associated with marked clinical variability, most children affected follow patterns of growth and development within the normal range. Some features of NF1 can be present at birth, but most manifestations emerge with age, necessitating periodic monitoring to address ongoing health and developmental needs and minimize the risk of serious medical complications. In this report, we provide a review of the clinical criteria needed to establish a diagnosis, the inheritance pattern of NF1, its major clinical and developmental manifestations, and guidelines for monitoring and providing intervention to maximize the health and quality of life of a child affected.

6.
Proteomics ; 19(11): e1800334, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30908848

RESUMO

Loss of NF1 is an oncogenic driver. In efforts to define pathways responsible for the development of neurofibromas and other cancers, transcriptomic and proteomic changes are evaluated in a non-malignant NF1 null cell line. NF1 null HEK293 cells were created using CRISPR/Cas9 technology and they are compared to parental cells that express neurofibromin. A total of 1222 genes and 132 proteins are found to be differentially expressed. The analysis is integrated to identify eight transcripts/proteins that are differentially regulated in both analyses. Metacore Pathway analysis identifies Neurogenesis NGF/TrkA MAPK-mediated signaling alterations. Next, the data set is compared with other published studies that involve analysis of cells or tumors deficient for NF1 and it is found that 141 genes recur in the sample and others; only thirteen of these genes recur in two or more studies. Genes/proteins of interest are validated via q-RT-PCR or Western blot. It is shown that KRT8 and 14-3-3σ protein levels respond to exogenously introduced mNf1 cDNA. Hence, transcripts/proteins that respond to neurofibromin levels are identified and they can potentially be used as biomarkers.

9.
Genet Med ; 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30190611

RESUMO

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

10.
Cancer Prev Res (Phila) ; 11(10): 655-664, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30104415

RESUMO

NF1 germline mutation predisposes to breast cancer. NF1 mutations have also been proposed as oncogenic drivers in sporadic breast cancers. To understand the genomic and histologic characteristics of these breast cancers, we analyzed the tumors with NF1 germline mutations and also examined the genomic and proteomic profiles of unselected tumors. Among 14 breast cancer specimens from 13 women affected with neurofibromatosis type 1 (NF1), 9 samples (NF + BrCa) underwent genomic copy number (CN) and targeted sequencing analysis. Mutations of NF1 were identified in two samples and TP53 were in three. No mutation was detected in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, and STK11 HER2 (ErbB2) overexpression was detected by IHC in 69.2% (9/13) of the tumors. CN gain/amplification of ERBB2 was detected in 4 of 9 with DNA analysis. By evaluating HER2 expression and NF1 alterations in unselected invasive breast cancers in TCGA datasets, we discovered that among samples with ERBB2 CN gain/amplification, the HER2 mRNA and protein expression were much more pronounced in NF1-mutated/deleted samples in comparison with NF1-unaltered samples. This finding suggests a synergistic interplay between these two genes, potentially driving the development of breast cancer harboring NF1 mutation and ERBB2 CN gain/amplification. NF1 gene loss of heterozygosity was observed in 4 of 9 NF + BrCa samples. CDK4 appeared to have more CN gain in NF + BrCa and exhibited increased mRNA expression in TCGA NF1--altered samples. Cancer Prev Res; 11(10); 655-64. ©2018 AACR.

11.
Genet Med ; 20(7): 671-682, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30006586

RESUMO

DISCLAIMER: This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is caused by a heterozygous loss-of-function variant in the tumor suppressor gene NF1; it affects ~1/1,900-1/3,500 people worldwide. The disorder is associated with an 8-15-year reduction in average life expectancy in both men and women, primarily due to malignant neoplasms and cardiovascular causes. METHODS: A work group of experts sought to determine the prevalence, morbidity and mortality, and available treatments of common and emerging NF1-related clinical problems in adults. Work-group members identified peer-reviewed publications from PubMed. Publications derived from populations and multi-institution cohorts were prioritized. Recommendations for management arose by consensus from this literature and the collective expertise of the authors. RESULTS: Malignant peripheral nerve sheath tumor (MPNST), breast cancer, cutaneous neurofibromas, and significant psychiatric and neurologic diagnoses are common problems in patients with NF1. CONCLUSION: Patient education and sensitization to worrisome signs and symptoms such as progressive severe pain (MPNST), changes in tumor volume (MPNST), new, unexplained neurologic symptoms (MPNST, brain tumors), and diaphoresis/palpitations (pheochromocytoma) are important. Although many issues in adults with NF1 can be managed by an internist or family physician, we strongly encourage evaluation by, and care coordination with, a specialized NF1 clinic.

13.
Hum Mutat ; 39(6): 816-821, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29522274

RESUMO

Neurofibromatosis type 1 (NF1) is caused by pathogenic variants or mutations in the NF1 gene that encodes neurofibromin. We describe here a new approach to determining the functional consequences of NF1 genetic variants. We established a heterologous cell culture expression system using a full-length mouse Nf1 cDNA (mNf1) and human cell lines. We demonstrate that the full-length murine cDNA produces a > 250 kDa neurofibromin protein that is capable of modulating Ras signaling. We created mutant cDNAs representing NF1 patient variants with different clinically relevant phenotypes, and assessed their ability to produce mature neurofibromin and restore Nf1 activity in NF1-/- cells. These cDNAs represent variants in multiple protein domains and various types of clinically relevant predicted variants. This approach will help advance research on neurofibromin structure and function, determine pathogenicity for missense variants, and allow for the development of activity assays and variant-directed therapeutics.

14.
Genes Chromosomes Cancer ; 57(1): 19-27, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28891274

RESUMO

NF1 mutations predispose to neurofibromatosis type 1 (NF1) and women with NF1 have a moderately elevated risk for breast cancer, especially under age 50. Germline genomic analysis may better define the risk so screening and prevention can be applied to the individuals who benefit the most. Survey conducted in several neurofibromatosis clinics in the United States has demonstrated a 17.2% lifetime risk of breast cancer in women affected with NF1. Cumulated risk to age 50 is estimated to be 9.27%. For genomic profiling, fourteen women with NF1 and a history of breast cancer were recruited and underwent whole exome sequencing (WES), targeted genomic DNA based and RNA-based analysis of the NF1 gene. Deleterious NF1 pathogenic variants were identified in each woman. Frameshift mutations because of deletion/duplication/complex rearrangement were found in 50% (7/14) of the cases, nonsense mutations in 21% (3/14), in-frame splice mutations in 21% (3/14), and one case of missense mutation (7%, 1/14). No deleterious mutation was found in the following high/moderate-penetrance breast cancer genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDH1, CHEK2, FANCC, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, TP53, and STK11. Twenty-five rare or common variants in cancer related genes were discovered and may have contributed to the breast cancers in these individuals. Breast cancer predisposition modifiers in women with NF1 may involve a great variety of molecular and cellular functions.


Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Neurofibromatose 1/genética , Sequenciamento Completo do Exoma , Adulto , Neoplasias da Mama/epidemiologia , Feminino , Genes da Neurofibromatose 1 , Humanos , Pessoa de Meia-Idade , Neurofibromatose 1/complicações , Oncogenes , Penetrância , Polimorfismo de Nucleotídeo Único
15.
J Child Neurol ; 33(1): 82-91, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29246097

RESUMO

Neurofibromatosis type 1 and type 2, affecting both children and adults, often results in devastating complications. The rapid unravelling of the genetic underpinnings of these unique disorders has led to the development of novel therapies, especially molecular-targeted therapies. To facilitate clinical trial development, the Neurofibromatosis Clinical Trial Consortium (NFCTC) was established in 2006 by the Department of Defense. Over the past decade, the Consortium has successfully completed studies for children and adults with neurofibromatosis type 1 and plexiform neurofibromas, neurocognitive challenges, low-grade gliomas, and malignant peripheral nerve sheath tumors. In addition, a study for children and adults with neurofibromatosis type 2 and acoustic schwannomas is near completion. The NFCTC has now been expanded to 19 sites in the United Stated and Australia. Mechanisms have been put in place to work closely with other consortia, foundations, and industry to expeditiously translate preclinical discoveries into clinical trials.


Assuntos
Ensaios Clínicos como Assunto , Neurofibromatoses/terapia , Animais , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/organização & administração , Comportamento Cooperativo , Humanos
18.
Curr Protoc Hum Genet ; 93: 10.1.1-10.1.9, 2017 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-28384400

RESUMO

Both cytogenetic and molecular genetic studies can contribute to the management of patients with cancer. In some cases, genetic markers are specific to particular tumor types and are useful in diagnosis. This can be helpful in distinguishing histologically similar tumors that may respond differently to treatment and can sometimes be of prognostic value. Genetic markers can also be tools for following the response of a tumor to therapy, providing a sensitive means to detect relapse. This introductory unit considers some of the types of genetic changes that occur in association with malignancies, as well as major approaches used in their detection. © 2017 by John Wiley & Sons, Inc.


Assuntos
Marcadores Genéticos/genética , Neoplasias/diagnóstico , Neoplasias/genética , Genes Supressores de Tumor , Marcadores Genéticos/efeitos dos fármacos , Humanos , Neoplasias/terapia , Oncogenes/genética , Patologia Molecular , Prognóstico
19.
Pediatr Rev ; 38(3): 119-128, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28250072

RESUMO

Neurofibromatosis (NF), including type 1 (NF1), type 2 (NF2), and schwannomatosis; tuberous sclerosis complex (TSC); and Sturge-Weber syndrome are 3 neurocutaneous disorders that typically present in childhood. Early recognition by the pediatrician can be critical to surveillance for treatable complications and genetic counseling. These conditions are diagnosed clinically, but genetic testing is available to clarify an uncertain diagnosis or help with genetic counseling. Although many of the complications can only be treated symptomatically, advances in understanding of the pathogenesis are opening new approaches to molecularly targeted therapeutics, which promise to alter the natural history of the conditions in the years to come.


Assuntos
Neurofibromatoses/diagnóstico , Síndrome de Sturge-Weber/diagnóstico , Esclerose Tuberosa/diagnóstico , Criança , Diagnóstico Diferencial , Testes Genéticos , Humanos , Neurofibromatoses/genética , Neurofibromatoses/terapia , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/terapia , Esclerose Tuberosa/genética , Esclerose Tuberosa/terapia
20.
Nat Rev Dis Primers ; 3: 17004, 2017 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-28230061

RESUMO

Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.


Assuntos
Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico , Neoplasias das Glândulas Suprarrenais/etiologia , Doenças do Desenvolvimento Ósseo/etiologia , Cognição , Diagnóstico Diferencial , Glioma/etiologia , Humanos , Neoplasias da Bainha Neural/etiologia , Neurofibromatose 1/fisiopatologia , Osteoporose/etiologia , Feocromocitoma/etiologia , Transtornos da Pigmentação/etiologia , Complexo Repressor Polycomb 2/genética , Qualidade de Vida/psicologia
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